1. Field of the Invention
The present invention pertains to a method for the preparation of putamen ovi, to putamen ovi having a defined grain size distribution, and to the use of putamen ovi for the treatment of various diseases. Additionally, the present invention pertains to the use of processed putamen ovi for the preparation of orally applicable medicaments and locally applicable bone replacement.
2. Review of Related Art
Egg shell as a medicament has been used since 1930. Formulations made of egg shells are still being used as a mineral and trace element supplying agent for the substitution of, in particular, calcium.
According to Rxc3x6mpp Chemielexikon, 9th edition, 1990, page 1079, item xe2x80x9cEierxe2x80x9d (xe2x80x9ceggsxe2x80x9d), the egg-shell of chicken eggs has a thickness of from 0.2 to 0.4 mm and is white or brown in color, depending on the breed. It is composed of a protein framework (protein-mucopolysaccharide complex) in which calcium carbonate as well as a minor amount of Ca and Mg salts are incorporated. The shell contains pores (7000-17,000 per egg) which are filled with protein fibers. The eggs of other bird species, such as goose, duck, pigeon or quail, are much less important than chicken eggs and are always indicated according to their origins. The shell has a dry mass content in the order of 98.4% which consists of 3.3% of proteins and 95.1% of minerals.
From SU 1 754 104, the use of egg-shells as a dentifrice is known. The use of this preparation is that of a dentifrice. It contains an allegedly caries-inhibiting film with reduced abrasive properties. This dentifrice contains only a very small and non-activity-determining proportion of egg-shells as an adjuvant. The egg-shell powder is not present as a monosubstance, but is embedded in sodium hydrogencarbonate (35-45% (m/m)) and is not taken up by the organism.
In CH 193 065 A, a liquid tonic is described which is rich in egg yolk, and thus particularly rich in cholesterol, and has high sugar and alcohol contents, but contains little egg-shell components. This is due to the preparation method. The finished emulsion contains from 2 to 3% of egg-shell components in the form of citratesxe2x80x94but only those which are dissolved or emulsified. This preparation contains only particular fractions of egg-shell. Due to its high proportion of cholesterol, sugar and alcohol, this tonic is not acceptable therapeutically in view of its clear potential of load on physiological feedback control systems.
According to FR-A-0 649 055, the egg-shells are sterilized with 20% ethylene oxide at 50 xc2x0 C. under a pressure of 5 atmospheres. This method enables a germ reduction rather than a complete sterilization which would be necessary to provide a product in conformity with the requirements of a human health product due to the presence of pathogenic bacteria, spores, etc. in the natural product egg shell.
The preparation described in GB 2 218 906 is employed for the treatment of dermal lesions. Finely ground egg-shells are processed into a preferably liquid formulation to be used orally or topically which in particular also includes essences, paraffin and various waxes and paraffin oils. The use of this preparation with eczema and allergic skin conditions is not acceptable for oral and topical application since egg-shells, due to their protein base, have a high allergenic potential themselves and may trigger typical skin irritations and increase existing syndromes of certain dermal lesions of allergic nature. Heating the egg-shells for sterilization by means of microwaves over a period of 6 minutes is inadequate for eliminating pathogens.
In EP 0 347 809 A2, a sterilization method for egg-shells is described. The sterilization method reported is unsuitable for eliminating the possible presence of pathogenic bacteria, spores, fungi and protozoans. The sterilization of egg-shell powder with dry air at 120xc2x0 C. for about 1 hour is not suitable for effecting a safe reduction of pathogenic germs and to counteract a loss in active ingredients. An increase in temperature, especially in the range of xe2x89xa7150xc2x0 C., for more than 1 hour destroys the biological carriers with membrane transit ability for an effective transport of minerals in compact and spongy substances. Following this thermal exposure, the egg-shell powder exhibits the biological effects of calcium carbonate with respect to the 45Ca incorporation rate.
Various formulations comprising egg-shell powder have been examined in U.S. Pat. No. 3,558,711, especially in rats with topical application on open wounds. An improved wound healing has been achieved as compared to the control animals. In this document, no suitable sterilization method is reported which would not affect the therapeutic effectiveness of the egg-shells. An oral application of egg-shell powder is not suggested in this patent.
In Chemical Abstracts, vol. 117, 1992, Ref. 33411x, egg-shell powder is processed into cosmetic preparations under the action of lactic acid. The calcium lactate products thus generated are embedded in a protein film. This lactate emulsion is processed into a cosmetic cream. In much the same way as preparation 1 (SU 1754 104), it only contains particular fractions of egg-shell which are topically applied.
In addition, there has been many decades of experience in the preparation of specialties, in particular in the sterilization without activity losses, namely: if a temperature of 80xc2x0 C. is exceeded in the sterilization of the egg-shell, then the biological carrier with membrane passage ability for the minerals is destroyed, so that the activity of the thermally destroyed product corresponds to that of calcium carbonate with respect to the 45Ca incorporation rate. On the other hand, this temperature alone is not sufficient to completely free the porous, heat-insulating raw material egg-shell/egg-shell powder from pathogenic bacteria, spores, fungi and protozoans the presence of which is to be expected due to fecal contamination, especially when in addition the storage conditions are unfavorable.
The prior art shows that the egg shell is formulated in the form of standardized, orally applicable preparations and is used for calcium substitution. However, there is still an need for an especially processed orally applicable medicament and locally applicable bone replacement.
According to the invention, it has been found that the use of putamen ovi surprisingly has advantages over the use of pure calcium carbonate in various conditions of disease. However, a particular problem in the use of putamen ovi as a medicament is to provide a standardized sterile medicament having a defined grain size.
In a first embodiment of the present invention, the above problem is solved by a method for the preparation of putamen ovi having a grain size of less than 0.1 mm wherein
a) egg-shells, especially from Gallus domesticus, are washed with water or an aqueous solution containing disinfectants and/or tensides with stirring at room temperature or elevated temperature;
b) the egg-shells having been cleaned from contaminants are subjected to a germ count reduction process or sterilization process;
c) the egg-shells are dried; and
d) the egg-shells are crushed to the desired grain size following or during the drying.
In another embodiment of this invention, an especially processed orally applicable medicament and locally applicable bone replacement is provided by the use of the central palisade zone of egg shells which is freed from the shell membrane, or from the shell membrane and the shell matrix, by proteases or alkaline denaturation, followed by purification, or by the use of the palisade matrix which is obtained either by decalcification or by means of aqueous and/or organic solvents, as well as by means of critical gases (CO2).
In yet another embodiment of this invention, methods are provided for the use of processed putamen ovi (egg shell of G. domesticus), in particular saccharide-containing granules of micronized egg shells (PO), egg shell components of the central palisade zone (POM), shell matrix with organically bound minerals (MPM), for the preparation of orally applicable medicaments for the treatment and prevention (protection) of organ and tissue damages caused by radiation (radioprevention, radioprotection), infections (infection prophylaxis) and chemically (chemoprevention, chemoprotection), especially of the O-MALT (mucosa associated lymphoid tissue) system of the small intestine (inflammatory diseases, Enteritis regionalis Crohn), the bone marrow (bone marrow aplasia), of bone and cartilage genesis disorders, of diseases of the locomotor system, of disease of the thymus (dysfunction, aplasia or hypoplasia), the spleen (dysfunction) and the lymph nodes (aplasia or hypoplasia due to medicament or radiation caused damages), the liver (atrophy, necrosis), the pancreas (insufficiency of the exocrine, secretory function of proteases, esterases, carbohydrases and nucleases, as well as insufficiency of the endocrine function of the islets of Langerhans and the carbohydrate metabolism) and the kidneys (insufficiency), and in general immunosuppressed conditions, for cellular immunostimulation, for the therapy of leucocytopenia, granulocytopenia, lymphocytopenia, thrombocytopenia, erythrocytopenia and in immunoglobulin deficiency conditions, also due to AIDS and tumors, as well as for the therapy of hyperlipoprotein-emias and hyperlipidemia; further, for the treatment of primary or secondary disorders or damages of chondral or desmal ossification, also in combination with sodium fluoride and hormones, especially estrogens (new generation estrogens, e.g., estrogen sulfamate), calcitonin, pyrophosphates (biphosphonates) and vitamins, especially vitamin D (D3 and dihydroxycholecalciferol), of the bony substance with external Substantia corticalis (lamellar bones) and internal Substantia spongiosa (framework of minute trabeculae) as well as bone marrow due to a reduction of all hematopoietic cell forms (bone marrow aplasia, depression or bone marrow metastases) due to a cytostatic or radiologic therapy or after radiation accidents, of the skeleton including osteocytes, intercellular substance with collagenous fibrils and calcified cement, of bone metabolism including the function of osteoclasts and osteoblasts, the balance between bone absorption and formation (bone tissue remodeling); for local and oral application for the reconstruction of bone deficiencies, in fracture healing, in the filling of bone damages after tumor operations, and for the removal of bone damages in oral surgery and plastic surgery of the face; further, for the treatment of bone necrosis due to irradiation and prolonged corticoid medication.